An objective is reducing the level (e.g., amount or concentration as measured before and after treatment) of circulating soluble urokinase receptor (suPAR) as therapy for kidney disease or its prevention.
Focal segmental glomerulosclerosis (FSGS) is a significant cause of end-stage kidney disease. It affects both native kidneys and transplanted kidney grafts. It starts in kidney glomeruli. In the early stage of FSGS, it mainly targets the visceral epithelium (also called podocytes) that comprise cells with foot processes to regulate functioning of the renal filtration barrier. Generally, effacement of podocyte foot processes marks the first ultrastructural step that is associated with loss of plasma proteins into the urine. While gene defects in podocytes have been identified for hereditary FSGS, there are also cases that occur in the absence of gene defects or with post-transplant recurrence in about 30% of patients receiving a kidney graft. These observations led to the suggestion that development of FSGS can be associated with a “FSGS permeability factor” in the patient's circulation (see Savin et al., Translational Res. 151:288-292, 2008). Both Staphylococcus protein A and galactose have high affinity for FSGS permeability factor. Ex vivo removal from the body of a subject by plasmapheresis or binding to staphylococcal protein A improved proteinuria in FSGS patients. When a patient with a nephrotic syndrome resistant to corticosteroids, immunosuppression, and plasmapheresis was administered oral galactose, his nephrotic syndrome went into remission for more than two years (De Smet et al., Nephrol. Dial. Transplant. 24:2938-2940, 2009). This led to the hypothesis that interactions between FSGS permeability factor in the circulation and galactose moieties on the glomerular glycocalyx might induce a nephrotic syndrome.
But in another case, there was no improvement of proteinuria when a dialysis-dependent patient was administered galactose (Savin et al., 2008). Plasmapheresis appears to have improved proteinuria only for a short time and required early intervention. Furthermore, molecular identification of FSGS permeability factor was uncertain because the equal effectiveness of its removal by protein A and ovine anti-human immunoglobulin, which implied the factor included an immunoglobulin determinant, appeared to contradict the determination of a molecular weight smaller than 100 kDa by size fractionation (Dantal et al., 3. Am. Soc. Nephrol. 9:1709-1715, 1998).
WO 2010/054189 disclosed a role for suPAR in pathogenesis of proteinuric kidney disease. But it did not disclose ex vivo removal of suPAR by an extracorporeal process as therapy and/or prevention of kidney disease. For the present invention, neutralizing antibodies are not necessarily needed.
Dantal et al. (1998) taught away from extracorporeal removal of FSGS permeability factor using an immunoaffinity cartridge by warning, “Plasma immunoadsorption on columns containing sheep anti-human immunoglobulins or protein A does not offer a realistic approach for treating FSGS patients because of its transient effect and its cost” (page 1715). Therefore, a longer lasting and less expensive technology to improve proteinuria and/or to avoid kidney failure was needed.
In a multi-center study, the concentration of suPAR has now been determined in sera collected from patients having glomerular disease. suPAR is significantly elevated in FSGS patients, and is found to possess characteristics of an FSGS permeability factor. The suPAR can now be removed from the circulation of a subject needing treatment to provide desirable therapy for kidney disease and/or its prevention.